Abstract Background: TGF-β drives immunosuppression and T-cell exclusion in solid tumors and contributes to ICI-acquired resistance. The integrins αvβ8 and αvβ1 activate latent TGF-β in the tumor microenvironment, promoting immune escape. PLN-101095 is a first-in-class, oral dual αvβ8/αvβ1 inhibitor designed to block TGF-β activation and restore antitumor immunity in patients with advanced solid tumors refractory to prior ICI (NCT06270706). Methods: This ongoing Phase 1a/1b, dose-escalation study evaluated PLN-101095 as monotherapy and in combination with pembrolizumab in patients with advanced solid tumors refractory to prior ICI. Primary objectives were safety and tolerability; secondary objectives included pharmacokinetics (PK), pharmacodynamics (PD), and preliminary antitumor activity. Patients received PLN-101095 monotherapy for 14 days, then pembrolizumab (200 mg Q3W) starting on D15. Accelerated titration (n=1) was permitted at 250 and 500 mg BID. Cohorts of ≥3 patients were enrolled at 1000 mg BID, 1000 mg TID, and 2000 mg BID. Results: Sixteen patients with nine advanced solid tumor types were enrolled. The population was predominantly white, with balanced sex distribution and median age of 60 years. Most patients (75%) were ICI secondary refractory, with median prior ICI exposure of 12 months and a median of 3 prior systemic therapies. The regimen was well tolerated; the most common treatment-emergent adverse event (TEAE) were grade 1-2 rash (50%), anemia, and diarrhea (18.8% each). Five SAEs occurred, two related to PLN-101095 (keratoacanthoma in cohort 1; immune-mediated hepatitis in cohort 3), the latter being the only dose-limiting toxicity. PLN-101095 showed dose-dependent PK with 24-hour αvβ8 IC90 coverage at doses ≥1000 mg BID. PD analyses reported increased plasma IFN-γ, CXCL9, and Granzyme B after monotherapy (D14) and combination therapy (D28). Among ICI-secondary-resistant patients at ≥1000 mg BID (n=10), antitumor activity included 1 complete response (MSI-high cholangiocarcinoma) and 3 partial responses (melanoma, NSCLC, HNSCC) by iRECIST, with a median time on treatment of 15 months. IFN-γ induction during monotherapy was significantly higher in responders vs. nonresponders (p<0.01 at D14, p<0.05 at D28) and correlated with increased soluble PD-L1; ctDNA was undetectable by week 10 in responders with baseline detectable ctDNA. Conclusion: PLN-101095 and pembrolizumab had durable antitumor activity in heavily pretreated ICI-secondary resistant tumors. Early systemic induction of IFN-γ emerged as a potential PD marker associated with clinical response and warrants further investigation. Based on these findings PLN-101095 is advancing to Part 1b, evaluating tumor-specific expansion cohorts in ICI-resistant populations. Citation Format: Timothy A. Yap, Andrae Vandross, Jenny Amaya-Amaya, Chris N. Barnes, Shuguang Ma, Martin Decaris, Keithryn Nicolas, Alexander Spira, Jacqueline Brown, Patricia LoRusso, Manish R. Sharma. First-in-human phase I study of PLN-101095, a first-in-class dual αvβ8/αvβ1integrin inhibitor, as monotherapy and in combination with pembrolizumab in patients with advanced solid tumors refractory to immune checkpoint inhibitors (ICI) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr CT002.

TPS2690 Background: Transforming growth factor-β (TGF-β) drives immunosuppression and T-cell exclusion in solid tumors and contributes to immune checkpoint inhibitor (ICI)-acquired resistance. The integrins α v β 8 and α v β 1 activate latent TGF-β in the tumor microenvironment, promoting immune escape. PLN-101095 is a first-in-class, oral dual α v β 8 /α v β 1 inhibitor designed to block TGF-β activation and restore antitumor immunity in patients with advanced solid tumors refractory to prior ICI. Part 1 of our study (NCT06270706) employed a Bayesian optimal interval design for dose escalation. The Part 2 expansion cohorts were driven by Part 1 efficacy signals, including 4 responders with secondary resistance to ICI, most of whom had high tumor mutational burden (TMB-H) prior to baseline. Methods: This is an ongoing Phase 1 open-label multicenter study conducted in the United States. Part 1 (dose escalation) enrolled patients with advanced or metastatic solid tumors who had either primary or secondary resistance to prior ICI. Part 2 (dose expansion) will enroll only patients meeting Society for Immunotherapy of Cancer (SITC) criteria for secondary resistance to prior ICI therapy based on a Simon 2-stage design. The Part 2 expansion cohorts will be as follows: 1) non-small cell lung cancer; 2) head and neck squamous cell carcinoma; 3) clear cell renal cancer; and 4) TMB-H tumors (historical ≥10 mutations/megabase, as determined by local testing with a Clinical Laboratory Improvement Amendments–certified next-generation sequencing [NGS] assay). The target sample size for cohorts 1-3 is 19 patients each, and the target for cohort 4 is 36 patients. The primary endpoints are objective response rate (ORR) and disease control rate (DCR) per immune RECIST. The secondary endpoints are pharmacokinetics (PK), safety and tolerability, and duration of response (DOR). Planned exploratory biomarkers analyses include characterization of integrin expression, TGF-β and immune-related gene expression, and tumor microenvironment (TME) in tumor biopsies. Plasma cytokine profiling and circulating tumor DNA (ctDNA) will also be examined. Clinical trial information: NCT06270706 .

Introduction Bexotegrast is an oral, once-daily, dual-selective inhibitor of integrins αvβ6 and αvβ1 in development for idiopathic pulmonary fibrosis (IPF). In the phase 2a study INTEGRIS-IPF study (NCT04396756), bexotegrast was well tolerated and showed antifibrotic activity.Methods and analysis BEACON-IPF (NCT06097260) is a randomised, double-blind, placebo-controlled, dose-finding, operationally seamless, adaptive phase 2b/3 study evaluating the efficacy and safety of bexotegrast over 52 weeks in participants with IPF. The phase 2b dose selection cohort will enrol 360 participants randomised 1:1:1 to once-daily bexotegrast 160 mg, 320 mg or placebo. After enrolling the last participant in the phase 2b cohort and while conduct is ongoing, the phase 3 cohort will immediately begin enrolment with a ‘seamless group’ using the same 1:1:1 randomisation. Once the phase 2b cohort has completed and a dose has been selected, the remainder of the phase 3 cohort will be enrolled. Participants in the phase 2b cohort receiving the non-selected dose will be eligible for an open-label study at the selected phase 3 dose. Background therapy with pirfenidone or nintedanib is permitted in ≤70% of the study population. Participants must be adults (≥40 years), have an IPF diagnosis ≤7 years per 2018 international guidelines, per cent predicted forced vital capacity (FVCpp) ≥45% and diffusing capacity for carbon monoxide (haemoglobin adjusted) ≥30%. The primary endpoint is change from baseline in absolute FVC at week 52. Additional endpoints include safety and tolerability, time to disease progression, participant-reported symptom assessments and quantitative lung fibrosis extent.Ethics and dissemination This study was approved by Advarra institutional review board (IRB; OHRP and Food and Drug Administration registration 00000971) and at each participating site by IRBs and local ethics review committees. Participants will provide written informed consent before taking part. Study results will be disseminated in peer-reviewed journals and international conferences targeted to medical, academic and patient communities.Trial registration number NCT06097260.

Rationale: Idiopathic pulmonary fibrosis (IPF) is characterized by excessive deposition of type I collagen. 68Ga-CBP8, a type I collagen positron emission tomography probe, measures collagen accumulation and shows higher collagen deposition in patients with IPF. Bexotegrast (PLN-74809) is an oral, once-daily, dual-selective inhibitor of αvβ6 and αvβ1 integrins under late-stage evaluation for treatment of IPF. Objectives: To evaluate changes in type I collagen in the lungs of participants with IPF after treatment with bexotegrast. Methods: In this phase 2 (NCT05621252), single-center, double-blind, placebo-controlled study, adults with IPF received bexotegrast 160 mg or placebo for 12 weeks. The primary endpoint was the change in whole-lung standardized uptake value of 68Ga-CBP8 positron emission tomography. Changes in lung dynamic contrast-enhanced magnetic resonance imaging parameters, FVC, cough severity, and biomarkers of collagen synthesis and progressive disease were also assessed. Measurements and Main Results: Of 10 participants, 7 received bexotegrast and 3 received placebo. At Week 12, the mean change from baseline in the top quartile of 68Ga-CBP8 whole-lung standardized uptake value was -1.2% with bexotegrast versus 6.6% with placebo; the greatest mean changes were observed in subpleural lung regions in both groups (bexotegrast, -3.7%; placebo, 10.3%). Dynamic contrast-enhanced magnetic resonance imaging showed numerically increased peak enhancement and faster contrast washout rate in bexotegrast-treated participants, suggesting improvements in lung microvasculature and decreased extravascular extracellular volume. Bexotegrast treatment resulted in numerical improvements in FVC, cough severity, and biomarkers. Conclusions: The reduced uptake of 68Ga-CBP8 in the lungs of participants with IPF indicates an antifibrotic effect of bexotegrast, suggesting the potential for favorable lung remodeling. Clinical trial registered with www.clinicaltrials.gov (NCT05621252).

Rationale: Idiopathic pulmonary fibrosis (IPF) is characterized by excessive deposition of type 1 collagen. 68Ga-CBP8, a type 1 collagen positron emission tomography (PET) probe, measures collagen accumulation and shows higher collagen deposition in patients with IPF. Bexotegrast (PLN-74809) is an oral, once-daily, dual-selective inhibitor of αvβ6 and αvβ1 integrins under late-stage evaluation for treatment of IPF. Objectives: Evaluate changes in type 1 collagen in the lungs of participants with IPF following treatment with bexotegrast. Methods: In this Phase 2 (NCT05621252), single-center, double-blind, placebo-controlled study, adults with IPF received bexotegrast 160mg or placebo for 12 weeks. Primary endpoint was the change in whole-lung standardized uptake value (SUV) of 68Ga-CBP8 PET. Changes in lung dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) parameters, forced vital capacity (FVC), cough severity, and biomarkers of collagen synthesis and progressive disease were also assessed. Measurements and Main Results: Of 10 participants, 7 received bexotegrast and 3 placebo. At Week 12, mean change from baseline in top quartile of 68Ga-CBP8 whole-lung SUV was −1.2% with bexotegrast vs 6.6% with placebo; greatest mean changes were observed in subpleural lung regions in both groups (bexotegrast, −3.7%; placebo, 10.3%). DCE-MRI demonstrated numerically increased peak enhancement and faster contrast washout rate in bexotegrast-treated participants, suggesting improvements in lung microvasculature and decreased extravascular extracellular volume. Bexotegrast treatment resulted in numerical improvements in FVC, cough severity, and biomarker levels. Conclusions: The reduced uptake of 68Ga-CBP8 in the lungs of participants with IPF indicates an antifibrotic effect of bexotegrast, suggesting the potential for favorable lung remodeling.

Rationale: Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive disease characterized by dyspnea and loss of lung function. Transforming growth factor-β (TGF-β) activation mediated by αv integrins is central to the pathogenesis of IPF. Bexotegrast (PLN-74809) is an oral, once-daily, dual-selective inhibitor of αvβ6 and αvβ1 integrins under investigation for the treatment of IPF. Positron emission tomography (PET) using an αvβ6-specific PET tracer could confirm target engagement of bexotegrast in the lungs of participants with IPF. Objectives: This Phase 2 study evaluated αvβ6 receptor occupancy in the lung as assessed by changes from baseline in αvβ6 PET tracer uptake, after single-dose administration of bexotegrast to participants with IPF. Methods: In this open-label, single-center study, adults with IPF received up to two single doses of bexotegrast, ranging from 60 to 320 mg with or without background IPF therapy (pirfenidone or nintedanib). At baseline and approximately 4 hours after each orally administered bexotegrast dose, a 60-minute dynamic PET-computed tomography scan was conducted after administration of an αvβ6-specific PET probe ([18F]FP-R01-MG-F2). αvβ6 receptor occupancy by bexotegrast was estimated from the changes in PET tracer uptake after bexotegrast administration. Pharmacokinetics, safety, and tolerability of bexotegrast were also assessed. Results: Eight participants completed the study. Total and unbound plasma bexotegrast concentrations increased in a dose-dependent manner, and regional PET volume of distribution values decreased in a dose- and concentration-dependent manner. The data for volume of distribution fit a simple saturation model, producing an unbound bexotegrast half maximal effective concentration estimate of 3.32 ng/ml. Estimated maximum receptor occupancy was 35%, 53%, 71%, 88%, and 92% after single 60-, 80-, 120-, 240-, and 320-mg doses of bexotegrast, respectively. No treatment-emergent adverse events related to bexotegrast were reported. Conclusions: Dose and concentration-dependent αvβ6 receptor occupancy by bexotegrast was observed by PET imaging, supporting once-daily 160- to 320-mg dosing to evaluate efficacy in clinical trials of IPF. Clinical trial registered with www.clinicaltrials.gov (NCT04072315).

BACKGROUND & AIMS:Transforming growth factor-β signaling activated by αvβ6 and αvβ1 integrins drives liver fibrosis in primary sclerosing cholangitis (PSC). The aim of this study was to investigate the safety and exploratory pharmacodynamics of bexotegrast (PLN-74809), an oral, once-daily inhibitor of αvβ6 and αvβ1 integrins, in participants with PSC and liver fibrosis. METHODS:In this phase II, double-blind, dose-ranging study, 117 participants with PSC were randomized 3:1 to receive once-daily oral bexotegrast or placebo in three cohorts: 40 mg or placebo for 12 weeks (part 1); 80 mg, 160 mg, or placebo for 12 weeks (part 2); and 320 mg or placebo for up to 40 weeks (part 3). The primary endpoint was the incidence of treatment-emergent adverse events (TEAEs). Exploratory pharmacodynamic endpoints included changes in alkaline phosphatase values, enhanced liver fibrosis (ELF) scores, neoepitope-specific N-terminal pro-peptide of type III collagen (PRO-C3) levels, liver stiffness measurements, gadoxetate-enhanced MRI measures, and the Itch Numeric Rating Scale. RESULTS:A total of 117 participants received bexotegrast (40 mg [n = 22], 80 mg [n = 21], 160 mg [n = 21], 320 mg [n = 27]) or placebo (n = 30). Bexotegrast was well tolerated, with similar rates of TEAEs in the pooled bexotegrast and placebo groups (72.7% and 70.0%). TEAEs were mild to moderate, and no serious TEAEs related to study drug were observed. Numerically less pharmacodynamic progression was observed with bexotegrast in ELF score, PRO-C3, and MRI assessments at Week 12 compared with placebo. Pharmacodynamic results at Week 24 showed limited change from Week 12 except in MRI parameters which continued to improve. CONCLUSIONS:Bexotegrast was well tolerated for up to 40 weeks in participants with PSC and liver fibrosis and was associated with numerically less progression in exploratory pharmacodynamic markers. IMPACT AND IMPLICATIONS:Primary sclerosing cholangitis (PSC) is a rare cholestatic disease of unknown etiology. Currently, there is an unmet medical need for safe and effective therapies capable of halting or reversing progression of PSC. In this phase II study in participants with PSC and suspected liver fibrosis, bexotegrast, an oral, once-daily, dual selective inhibitor of αvβ6 and αvβ1 integrins, had a favorable safety and tolerability profile. This study supports targeting integrin-mediated transforming growth factor-β activation as a potential therapeutic approach for PSC. TRIAL REGISTRATION NUMBER:NCT04480840.

What is this summary about? This plain language summary shares results from a clinical study called INTEGRIS-IPF that was published in the American Journal of Respiratory and Critical Care Medicine in 2024. This study looked at a medicine called bexotegrast (beck-so-teh-grast) as a possible treatment for idiopathic pulmonary fibrosis (i-dee-uh-pa-thick pul-muh-ner-ee fie-bro-sis; IPF). Bexotegrast is an investigational medicine, which means that it is being studied and has not yet been approved by the US Food and Drug Administration (FDA), for people with IPF to take as a treatment. IPF is a chronic, progressive lung disease that makes it hard to breathe and gets worse over time. There is no cure for IPF, treatment includes symptom management and consideration for the use of nintedanib or pirfenidone , which may decrease the pace of disease progression. The study compared bexotegrast to a placebo (a treatment that looks identical to the medicine but has no medicinal effect) to look at how well it works and how safe it is in treating people with IPF. Most people in the study also took one of two medicines that are already approved by the FDA for IPF, pirfenidone or nintedanib .

Rationale: Idiopathic pulmonary fibrosis (IPF) is a rare and progressive disease that causes progressive cough, exertional dyspnea, impaired quality of life, and death. Objectives: Bexotegrast (PLN-74809) is an oral, once-daily, investigational drug in development for the treatment of IPF. Methods: This Phase-2a multicenter, clinical trial randomized participants with IPF to receive, orally and once daily, bexotegrast at 40 mg, 80 mg, 160 mg, or 320 mg, or placebo, with or without background IPF therapy (pirfenidone or nintedanib), in an approximately 3:1 ratio in each bexotegrast dose cohort, for at least 12 weeks. The primary endpoint was incidence of treatment-emergent adverse events (TEAEs). Exploratory efficacy endpoints included change from baseline in FVC, quantitative lung fibrosis (QLF) extent (%), and changes from baseline in fibrosis-related biomarkers. Measurements and Main Results: Bexotegrast was well tolerated, with similar rates of TEAEs in the pooled bexotegrast and placebo groups (62/89 [69.7%] and 21/31 [67.7%], respectively). Diarrhea was the most common TEAE; most participants with diarrhea also received nintedanib. Participants who were treated with bexotegrast experienced a reduction in FVC decline over 12 weeks compared with those who received placebo, with or without background therapy. A dose-dependent antifibrotic effect of bexotegrast was observed with QLF imaging, and a decrease in fibrosis-associated biomarkers was observed with bexotegrast versus placebo. Conclusions: Bexotegrast demonstrated a favorable safety and tolerability profile, up to 12 weeks for the doses studied. Exploratory analyses suggest an antifibrotic effect according to FVC, QLF imaging, and circulating levels of fibrosis biomarkers. Clinical trial registered with www.clinicaltrials.gov (NCT04396756).

Background Analyses of transforming growth factor-β (TGF-β) expression in tumors treated with immune checkpoint inhibitors (ICIs) suggest that in the tumor microenvironment may play a role in poor response to ICIs. PLN-101095 is a novel, orally bioavailable small molecule that inhibits integrin αvβ8 and αvβ1 binding to the latency-associated peptide of TGF-β, prevents its activation, and enhances the of ICIs including CD8+ T-cell infiltration in preclinical models. Methods A Phase 1a, first in human, dose-escalation, consecutive-cohort, open-label study was designed to evaluate the safety, tolerability and pharmacokinetics of PLN-101095 as monotherapy and in combination with pembrolizumab in patients with advanced or metastatic solid tumors progressing on treatment with pembrolizumab. Eligible patients must be ≥ 18 years, have received at least 3 doses (200 mg Q3W) of , have evidence of disease progression at least 3 months after initiation of , and no other available effective treatment options. PLN-101095 will be administered as a lead-in monotherapy for 14 days, followed by PLN-101095 in combination with pembrolizumab starting on Day 15. Dose-escalation will be determined by a Bayesian optimal interval dose escalation design with accelerated titration (n = 1) permitted for dose levels 1 and 2 (figure 1). A minimum of 3 participants will be accrued to dose levels 3 to 5. Following the dose-escalation cohorts, dose-expansion cohorts using a Simon's 2-stage design are planned. Conclusions This first-in-human trial will evaluate the safety and tolerability of PLN-101095, administered first as monotherapy to re-sensitize participants' tumors to pembrolizumab, and subsequently in combination with pembrolizumab. Enrolled patients will have demonstrated primary or acquired resistance to pembrolizumab and for assessing anti-tumor activity and pharmacodynamic effects. This trial design enables the efficient conduct of dose escalation trials involving ICI-sensitizing drugs in patients with resistance to ICIs. Ethics Approval The protocol and all amendments are approved by the appropriate institutional review board or independent ethics committee at each participating study site. The study is being conducted in accordance with the principles of the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines.

Background: Overexpression of integrins αvβ6 and αvβ1 activates latent TGF-β in IPF. Bexotegrast (PLN-74809), an oral, once-daily, dual-selective inhibitor of αvβ6 and αvβ1, may provide a novel IPF treatment via localized TGF-β inhibition. Aims and objectives: Report long-term safety and tolerability, and durability of effects on FVC and fibrotic markers for bexotegrast 320 mg. Methods: Participants were randomized: bexotegrast 320 mg (n=21) or placebo (n=8) for at least 24 but less than 48 weeks. Primary endpoints: safety and tolerability. Exploratory endpoints: change in FVC and Quantitative Lung Fibrosis (QLF) score at Week 24. Results: No drug-related serious treatment-emergent adverse effects (TEAEs) occurred: most were mild and unrelated to study drug. The most common TEAE was diarrhea (31.8% bexotegrast, 37.5% placebo), mainly observed in participants on background therapy. No discontinuations occurred due to TEAEs after Week 12. Through Week 40, serious AEs (SAEs) occurred in 9.1% (bexotegrast) and 12.5% (placebo): one fatal SAE (bexotegrast) was unrelated to study drug (acute respiratory failure, following a cardiac ablation). FVC decline was reduced in bexotegrast-treated participants vs. placebo at Week 12, with 50% of participants on bexotegrast showing improvement at Week 24. 89% of bexotegrast participants with improvement in FVC at Week 12 maintained this at Week 24. At Week 24, 71% of bexotegrast participants had stable/improved disease by QLF vs. 33% on placebo. Conclusions: Bexotegrast 320 mg showed favorable safety and tolerability up to 40 weeks, and physiologic and radiographic evidence of an antifibrotic effect up to Week 24. Phase 2b evaluation is planned for mid-2023.

BACKGROUND:This study assessed the efficacy and safety of velusetrag-a 5-HT4 agonist with pan-gastrointestinal prokinetic activity-for gastroparesis symptom management and gastric emptying (GE).METHODS:In this multicenter, double-blind, randomized, placebo-controlled study, subjects with diabetic or idiopathic gastroparesis received velusetrag 5, 15, or 30 mg or placebo for 12 weeks. The primary efficacy outcome was a 7-day mean Gastroparesis Cardinal Symptom Index 24-h composite score (GCSI-24H) change from baseline at week 4; GE was evaluated using scintigraphy (GES) and breath tests, and safety from adverse events (AEs).KEY RESULTS:232 subjects (183 females; 113 idiopathic gastroparesis) received treatment from February 2015 through June 2017. Least-squares mean improvement from baseline GCSI-24H (primary endpoint) at week 4 was -1.5 following velusetrag 5 mg vs -1.1 following placebo (treatment difference, -0.4; 95% confidence interval, -0.75 to -0.03; nominal p = 0.0327; Hochberg-adjusted p = 0.0980 [not significant]). Symptom improvement from baseline was achieved only with velusetrag 5 mg, which resulted in greater improvement from baseline vs placebo in all gastroparesis core symptoms, especially in subjects with idiopathic gastroparesis. Improvement from baseline GE by GES was greater in subjects receiving velusetrag (all doses) vs placebo; >70% of subjects receiving velusetrag 30 mg had GE normalization at 4 h. Treatment-emergent AEs were generally mild.CONCLUSIONS AND INFERENCES:Velusetrag treatment was generally well-tolerated and associated with improved GE vs placebo in subjects with diabetic or idiopathic gastroparesis; however, only the lowest dose, velusetrag 5 mg, was associated with short-term improvement in gastroparesis symptoms.CLINICALTRIALS:GOV: NCT02267525.

LINKED CONTENTThis article is linked to Kuo et al papers. To view these articles, visit https://doi.org/10.1111/apt.16344 and https://doi.org/10.1111/apt.16395

Context: Congenital adrenal hyperplasia due to 21-hydroxylase deficiency (21OHD) is typically treated with lifelong supraphysiologic doses of glucocorticoids (GCs). Tildacerfont, a corticotropin-releasing factor type-1 receptor antagonist, may reduce excess androgen production, allowing for GC dose reduction. Objective: Assess tildacerfont safety and efficacy. Design and Setting: Two Phase 2 open-label studies. Patients: Adults with 21OHD. Intervention: Oral tildacerfont 200 to 1000 mg once daily (QD) (n=10) or 100 to 200 mg twice daily (n=9 and 7) for 2 weeks (Study 1), and 400 mg QD (n=11) for 12 weeks (Study 2). Main Outcome Measure: Efficacy was evaluated by changes from baseline at 8 am in adrenocorticotropic hormone (ACTH), 17-hydroxyprogesterone (17-OHP), and androstenedione (A4) according to baseline A4 <= 2x upper limit of normal (ULN) or A4>2x ULN. Safety was evaluated using adverse events (AEs) and laboratory assessments. Results: In Study 1, evaluable participants with baseline A4>2x ULN (n=11; 19-67 years, 55% female) had reductions from baseline in ACTH (-59.4% to -28.4%), 17-OHP (-38.3% to 0.3%), and A4 (-24.2% to -18.1%), with no clear dose response. In Study 2, participants with baseline A4>2x ULN (n=5; 26-63 years, 40% female) had similar to 80% maximum mean reductions in biomarker levels. ACTH and A4 were normalized for 60% and 40%, respectively. In both studies, participants with baseline A4 <= 2x ULN maintained biomarker levels. AEs (in 53.6% of patients overall) included headache (7.1%) and upper respiratory tract infection (7.1%). Conclusions: For patients with 21OHD, up to 12 weeks of oral tildacerfont reduced or maintained key hormone biomarkers toward normal.

Summary Background Gastroparesis is a serious gastrointestinal (GI) condition characterised by delayed gastric emptying (GE). Velusetrag—a potent, selective, pan‐gastrointestinal 5‐hydroxytryptamine type 4 receptor agonist—is under investigation for treatment of GI motility disorders including gastroparesis. Aims To assess the efficacy and safety of velusetrag for accelerating GE in subjects with diabetic or idiopathic gastroparesis. Methods In this multicentre, randomised, double‐blind, placebo‐controlled, three‐period fixed‐sequence crossover phase 2 study, subjects with diabetic or idiopathic gastroparesis received oral velusetrag (5, 15 or 30 mg) or placebo once daily for 7 days each. The primary outcome was proportion of subjects achieving ≥20% reduction in GE half‐time (GE t 1/2 ) from each treatment period baseline on day 7. Absolute and percent changes from baseline GE t 1/2 were also assessed. GE was measured using a [ 13 C]‐octanoate breath test. Safety was evaluated from treatment‐emergent adverse events (TEAEs). Results Thirty‐four subjects (67.6% female; mean age, 46.3 years; 52.9% with diabetic gastroparesis) were included. Treatment with velusetrag 30 mg significantly increased the proportion of subjects with ≥20% reduction from baseline GE t 1/2 compared with placebo (52% vs 5%, P = 0.002), and GE t 1/2 was numerically reduced following all three doses of velusetrag relative to placebo treatment. Efficacy was similar between subjects with diabetic and idiopathic gastroparesis. Velusetrag treatment was generally well tolerated; most TEAEs were mild and related to GI transit acceleration. Conclusions Velusetrag accelerates GE in subjects with diabetic or idiopathic gastroparesis and is generally well tolerated in this population (Clinicaltrials.gov NCT01718938).